Methods of treating factor VIIa-associated conditions with compounds having an amine nucleus

ABSTRACT

Methods of treating Factor VIIa-associated conditions in a mammal are described, comprising administering to the mammal in need of treatment thereof an effective amount of at least one compound having the formula (I),  
                 
 
     or a pharmaceutically-acceptable salt, hydrate or prodrug thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the priority benefit of U.S.Provisional Application No. 60/389,833, filed Jun. 19, 2002, which isexpressly incorporated fully herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to methods of treating conditionsassociated with the activity of Factor VIIa comprising administration ofcompounds having an amine nucleus, as further defined herein. Theinvention further relates to select compounds having surprisinglyadvantageous activity in inhibiting Factor VIIa.

BACKGROUND OF THE INVENTION

[0003] An elevated blood plasma level of Factor VIIa is a risk factorfor cardiovascular disease and abnormalities of the coagulation system.Uncontrolled FVIIa activation can lead to occlusive arterial thrombosisand thromboembolism which can produce unstable angina, myocardialinfarction, and stroke. It is estimated that this year 1.1 millionAmericans will have a new or secondary heart attack, and about one thirdof them will die. This makes arterial thrombotic diseases the singleleading cause of death in America. Stroke killed an estimated 158,000people in 1995 and is the third largest cause of death (ranking behindheart disease and all forms of cancer). Stroke is also the singleleading cause of disability in the United States.

[0004] Thrombosis in the veins deep in thighs or calves (deep veinthrombosis) can lead to ischemia, pain, tenderness, and discoloration ofthe affected area. A major complication of venous thrombosis ispulmonary embolism, i.e., a clot breaks free and travels through thevenous circulation and right heart to the pulmonary circulation, whereit blocks an artery of the lung. Pulmonary function is compromised anddeath may follow. It is estimated that there are about 50,000 deaths peryear resulting from pulmonary embolism (Moser, 1990).

[0005] FVIIa activation can also result from gram-negative bacteremiawhich causes half of the cases of lethal septic shock acquired duringhospitalization. Bacterial lipopolysaccharide (LPS) and inflammatorymediators mediate some of the sequelae including a coagulopathy that maybe triggered by expression of tissue factor (TF) on macrophages andendothelial cells.

[0006] Accordingly, antithrombotic agents have been researched anddeveloped for use in treating cardiovascular and other diseases.Presently, antithrombotic agents include heparin, coumarin, and aspirin,among others. There are, however, limitations with these agents. Forexample, both heparin and coumarin have a highly-variable dose-relatedresponse, and their anticoagulant effects must be closely monitored toavoid a risk of serious bleeding. The erratic anticoagulant response ofheparin is likely due to its propensity to bind non-specifically toplasma proteins. Aspirin has a limited efficacy and at high dosespresents a risk of gastrointestinal bleeding. Thrombin inhibitors andtheir drawbacks are further discussed in WO 96/20689 to duPont MerckPharmaceutical Co.

[0007] As may be appreciated, those in the field of pharmaceuticalresearch continue to seek to develop new compounds and compositionshaving increased effectiveness and bioavailability and/or having fewerside effects. There is particularly an interest in developing agentsthat can selectively and directly inhibit key factors in the complicatedcoagulation process. The present invention provides compounds useful asinhibitors of Factor VIIa. Amino-based compounds useful as IMPDHinhibitors are disclosed in U.S. Pat. No. 6,399,773, and compoundsuseful as IMPDH inhibitors and Factor VIIa inhibitors are disclosed inU.S. Pat. application Ser. No. 09/997,963, filed Nov. 29, 2001, acontinuation-in-part application to U.S. Pat. application Ser. No.09/428,432. Additionally, compounds useful in treating Factor VIIaconditions are described in U.S. provisional application Ser. No.60/389,832, titled “Ureido-Substituted Aniline Compounds Useful AsSerine Protease Inhibitors,” filed Jun. 19, 2002, with common inventorsherein and assigned to the present assignee. Each of the patents, patentapplications, and articles cited herein are incorporated herein byreference.

SUMMARY OF THE INVENTION

[0008] The instant invention comprises methods of treating FactorVIIa-associated conditions in a mammal comprising administering to themammal in need of treatment thereof, an effective amount of at least onecompound having the formula (I),

[0009] or a pharmaceutically-acceptable salt, hydrate or prodrugthereof, wherein:

[0010] A is a five or six-membered saturated or unsaturated carbocyclic,heterocyclic or heteroaryl ring, said ring A being optionallysubstituted with up to three groups selected from R₂₇;

[0011] B is selected from one of

[0012] D is phenyl, cycloalkyl, or a five to six-membered heteroaryl orheterocyclo, provided, however, that when A is a heterocyclo orheteroaryl and a is 1, then D is phenyl or cycloalkyl;

[0013] R₁ is hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted with one totwo R₂₁;

[0014] R₂ and R₃ are attached to any available carbon atom of ring B andring D, respectively, and at each occurrence are independently selectedfrom halogen, cyano, NO₂, C₁₋₆alkyl, substituted C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, haloalkyl, haloalkoxy, —OR₁₅, —C(═O)R₁₅, —OC(═O)R₁₅,—CO₂R₁₅, —OCO₂R₁₅, —C(═O)NR₁₅R₁₆, —OC(═O)NR₁₅R₁₆, —NR₁₅R₁₆,—NR₁₆C(═O)R₁₅, —NR_(16a)C(═O)NR₁₅R₁₆, —NR₁₆CO₂R₁₅, —SR₁₅, —S(O)R₁₅,—SO₂R₁₅, —SO₂NR₁₅R₁₆, —SO₃R₁₅, —NR₁₆SO₂R₁₅, and —NR_(16a)SO₂NR₁₅R₁₆;

[0015] R₄ and R₅ are independently selected from hydrogen, halogen,hydroxy, cyano, C₁₋₃alkoxy, —OCF₃, CF₃, amino, C₁₋₆alkylamino,C₁₋₄alkyl, and C₁₋₄alkyl substituted with one to two R₂₂; oralternatively, R₄ and R₅ taken together may form a 3-8 memberedcycloalkyl or heterocyclic spiro ring, said ring being optionallysubstituted with up to three R₂₈;

[0016] R₆ is hydrogen, C₁₋₄alkyl, or C₁₄alkyl substituted with one totwo R₂₃;

[0017] R₇ and R₈ are independently selected from hydrogen, halogen,hydroxy, cyano, C₁₃alkoxy, —OCF₃, CF₃, amino, C₁₋₆alkylamino, C₁₋₄alkyl,and C₁₋₄alkyl substituted with one to two R₂₄; or alternatively, R₇ andR₈ taken together may form a 3-8 membered cycloalkyl or heterocyclicspiro ring, said ring being optionally substituted with up to three R₂₉;or alternatively, one or both of R₇ and R₈ may be taken together withone or both of R₉ and R₁₀ to form a heterocyclic or heteroaryl ring,said ring in turn being optionally substituted with up to three R₃₀;

[0018] R₉ and R₁₀are independently selected from hydrogen, C₁₋₄alkyl,and C₁₋₄alkyl substituted with one to two R₂₅; or alternatively, R₉ andR₁₀ taken together may form a 3-8 membered heterocyclic ring or a fiveto six membered heteroaryl ring, said ring being optionally substitutedwith up to three R₃₀; or alternatively, one or both of R₉ and R₁₀may betaken together with one or both of R₇ and R₈ to form a heterocyclic orheteroaryl ring, said ring being optionally substituted with up to threeR₃₀;

[0019] R₁₁ at each occurrence is independently selected from halogen,cyano, NO₂, C₁₋₆alkyl, substituted C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,haloalkyl, haloalkoxy, —OR₁₃, —C(═O)R₁₃, —OC(═O)R₁₃, —CO₂R₁₃, —OCO₂R₁₃,—C(═O)NR₁₃R₁₄, —OC(═O)NR₁₃R₁₄, —NR₁₃R₁₄, —NR₁₄C(═O)R_(13a), —NR₁₄CO₂R₁₃,—SR₁₃, —S(O)R₁₃ , —SO₂R₁₃, —SO₂NR₁₃R₁₄, —SO₃R₁₃, —NR₁₄SO₂R₁₃, and—NR_(14a)SO₂NR₁₃R₁₄; or alternatively, two R₁₁ groups may be takentogether to form a fused benzo, heteroaryl, or heterocyclic ring,wherein said ring in turn is optionally substituted with up to one Agroup and/or one to two R₃₁; provided, however, that R₁₁is not alkylsubstituted with —NR_(18a)C(═O)NR₁₇R₁₈;

[0020] R₁₃, R₁₄, and R_(14a) at each occurrence independently of eachother are selected from hydrogen, C₁₋₆alkyl, substituted C₁₋₆alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, C₃₋₁₀cycloalkyl(C₀₋₄alkyl), aryl(CO₀₋₄alkyl),heterocyclo(C₀₋₄alkyl), and heteroaryl(CO ₀₋₄alkyl), wherein each ofsaid cycloalkyl, aryl, heterocyclo, and heteroaryl groups are optionallysubstituted with up to two substituents independently selected from R₃₂;provided, however, that when R₁₃ is attached to a sulfonyl group as in—SO₂R₁₃, —S(═O)R₁₃, and —SO₃R₁₃, then R₁₃ is not hydrogen; oralternatively, R₁₃ and R₁₄ can be taken together with the nitrogen atomto which they are attached to form a heterocyclo or heteroaryl, saidring being in turn optionally substituted with up to three groupsselected from R₃₂;

[0021] R_(13a)is selected from hydrogen, C₁₋₆alkyl, substitutedC₁₋₆alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, C₃₋₁₀cycloalkyl(C₀₋₄alkyl),aryl(C₀₋₄alkyl), heterocyclo(C₁₋₄alkyl), and heteroaryl(C₁₋₄alkyl),wherein each of said cycloalkyl, aryl, heterocyclo, and heteroarylgroups are optionally substituted with up to two substituentsindependently selected from R₃₂;

[0022] R₁₅ at each occurrence independently of each other R₁₅ isselected from hydrogen, C₁₋₆alkyl, substituted C₁₋₆alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, C₃₋₁₀cycloalkyl(C₀₋₄alkyl), aryl(C₀₋₄alkyl),heterocyclo(C₀₋₄alkyl), and heteroaryl(C₀₋₄alkyl), wherein each of saidcycloalkyl, aryl, heterocyclo, and heteroaryl groups are optionallysubstituted with up to two substituents independently selected from R₃₃;provided, however, that when R₁₅ is attached to a sulfonyl group as in—SO₂R₁₅, —S(═O)R₁₅, and —SO₃R₁₅, then R₁₅ is not hydrogen;

[0023] R₁₆ and R_(16a) at each occurrence independently of each otherR₁₆ and R_(16a) are selected from hydrogen, C₁₋₆alkyl, substitutedC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, —OR₁₉, —C(═O)R₁₉, —CO₂R₁₉, —SO₂R₁₉,C₃₋₁₀cycloalkyl(C₀₋₄alkyl), aryl(C₀₋₄alkyl), heterocyclo(C₀₋₄alkyl), andheteroaryl(C₀₋₄alkyl), wherein R₁₉ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, aryl,heterocyclo, or heteroaryl, and each of said R₁₉, cycloalkyl, aryl,heterocyclo, and heteroaryl groups are in turn optionally substitutedwith up to two substituents independently selected from R₃₄;

[0024] alternatively, R₁₅ and R₁₆ can be taken together with thenitrogen atom to which they are attached to form a heterocyclo orheteroaryl, said ring being in turn optionally substituted with up tothree groups selected from R₃₄;

[0025] R₁₇ and R₁₈ are independently selected from hydrogen, alkyl,substituted alkyl, cyano, hydroxy, alkoxy, cycloalkyl, heterocyclo, aryland heteroaryl, or taken together may form a heteroaryl or heterocycloring;

[0026] R_(17a) is hydrogen, alkyl, or substituted alkyl;

[0027] R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, and R₂₆ are independently selected fromhalogen, cyano, hydroxy, C₁₋₃alkoxy, OCF₃, CF₃, amino, andC₁₋₆alkylamino;

[0028] R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₄ are at each occurrenceindependently selected from C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, oxo(═O), halo(C₀₋₄alkyl), NO₂(C₀₋₄alkyl), hydroxy(C₀₋₄alkyl),CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl), cyano(C₀₋₄alkyl), amino(C₀₋₄alkyl),C₁₋₄ alkoxy(C₀₋₄alkyl), C₁₋₆alkylamino(C₀₋₄alkyl), C₁₋₄alkylthio(C₀₋₄alkyl), carbamyl(C₀₋₄alkyl),—C(═O)C₁₋₄ alkyl, —CO₂C₁₋₄alkyl, —S(O)(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄alkyl),—SO₃H, —SO₃(C₁₋₄alkyl), —NHCO(C₁₋₆alkyl), and —C(═O)NH(C₁₋₄alkyl),provided, however, that when R₂₆, R₂₇, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₄ aresubstituents attached to an aryl or heteroaryl ring, said groups are notselected from oxo (═O); provided further, that when R₂₆, R₂₇, R₃₀, R₃₁,R₃₂, R₃₃, and R₃₄ are hydroxy and attached to an aryl or heteroarylring, the ring may undergo tautomerization to an oxo species, or existas an equilibrium mixture of both tautomers;

[0029] a is 0 or 1;

[0030] m is 0, 1, or 2;

[0031] n is 0, 1, 2, 3, or 4;

[0032] p is 0, 1 or 2; and

[0033] q is 0, 1, 2, 3 or 4.

[0034] Also included within the scope of the present invention areselect compounds having surprisingly advantageous activity in inhibitingFactor VIIa.

DETAILED DESCRIPTION OF THE INVENTION

[0035] The following are definitions of terms used in thisspecification. The initial definition provided for a group or termherein applies to that group or term throughout this specification,individually or as part of another group, unless otherwise indicated.

[0036] The term “alkyl” refers to straight or branched chain hydrocarbongroups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms.Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, aremost preferred.

[0037] The term “substituted alkyl” refers to an alkyl group as definedabove having one, two, or three substituents selected from the groupconsisting of halogen, trifluoromethyl, trifluoromethoxy, alkenyl,alkynyl, nitro, cyano, keto (═O), —OR_(a), —SR_(a), —NR_(a)R_(b),—NR_(a)SO₂R_(c), —SO₂R_(c), —SO₂NR_(a)R_(b), —CO₂R_(a), —C(═O)R_(a),—C(═O)NR_(a)R_(b), —OC(═O)R_(a), —OC(═O)NR_(a)R_(b), —NR_(a)C(═O)R_(b),—NR_(a)CO₂R_(b), cycloalkyl, heterocyclo, aryl, and heteroaryl, whereinR_(a) and R_(b) are independently selected from hydrogen, alkyl,alkenyl, cycloalkyl, heterocyclo, aryl, and heteroaryl, and R_(c) isselected from alkyl, alkenyl, cycloalkyl, heterocyclo, aryl andheteroaryl. When a substituted alkyl (and/or R_(a), R_(b) and R_(c))includes a cycloalkyl, heterocyclo, aryl, or heteroaryl substituent,said ringed systems are as defined below and thus may in turn have zeroto three substituents (preferably 0-2 substituents), also as definedbelow. When R_(a), R_(b) or R_(c) is an alkyl or alkenyl, said alkyl oralkenyl may optionally be substituted with 1-3 of halogen,trifluoromethyl, trifluoromethoxy, nitro, cyano, keto (═O), OH,—O(alkyl), phenyloxy, benzyloxy, SH, —S(alkyl), NH₂, —NH(alkyl),—N(alkyl)₂, —NHSO₂(alkyl), —SO₂(alkyl), —SO₂NH₂, —SO₂NH(alkyl),—SO₂N(alkyl)₂, —CO₂H, —CO₂(alkyl), —C(═O)H, —C(═O)alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —OC(═O)alkyl, —OC(═O)NH₂,—OC(═O)NH(alkyl), —NHC(═O)alkyl, and/or —NHCO₂(alkyl).

[0038] When the term “alkyl” is used in conjunction with another groupsuch as in “arylalkyl” or “cycloalkylalkyl,” such reference is intendedto refer to a substituted alkyl in which at least one of thesubstituents is the specifically-named group, i.e., the group is bondedthrough an alkyl chain. For example, the term arylalkyl includes benzyl,or any other straight or branched chain substituted alkyl having atleast one aryl group attached at any point of the alkyl chain. However,it should be understood that when the term “alkyl” is used following abivalent linker preceeded by a bond designation, such as—C(═O)C₁₋₄alkyl, —S(O)C₁₋₄alkyl, —CO₂C₁₋₄alkyl, and —SO₂C₁₋₄alkyl, suchreferences are intended to mean that the alkyl group is attached via thelinker.

[0039] The term “alkenyl” refers to straight or branched chainhydrocarbon groups having 2 to 12 carbon atoms and at least one doublebond. Alkenyl groups of 2 to 6 carbon atoms and having one double bondare most preferred.

[0040] The term “alkynyl” refers to straight or branched chainhydrocarbon groups having 2 to 12 carbon atoms and at least one triplebond. Alkynyl groups of 2 to 6 carbon atoms and having one triple bondare most preferred.

[0041] The term “alkylene” refers to bivalent straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbonatoms, e.g., {—CH₂—}_(n), wherein n is 1 to 12, preferably 1-8. Loweralkylene groups, that is, alkylene groups of 1 to 4 carbon atoms, aremost preferred. The terms “alkenylene” and “alkynylene” refer tobivalent radicals of alkenyl and alknyl groups, respectively, as definedabove.

[0042] When reference is made to a substituted alkylene, alkenylene, oralkynylene group, these groups are substituted with one to threesubstitutents as defined above for alkyl groups. A substituted alkylene,alkenylene, or alkynylene may have a ringed substituent attached in aspiro fashion as in

[0043] and so forth.

[0044] The term “alkoxy” refers to an alkyl, alkenyl, substituted alkyl,or substituted alkenyl group bonded through an oxygen atom (—O—). Forexample, the term “alkoxy” includes the groups —O—C₁₋₁₂alkyl,—O—C₂₋₈alkenyl, —S—CH₂aryl, and so forth.

[0045] The term “alkylthio” refers to an alkyl, alkenyl, substitutedalkyl, or substituted alkenyl group bonded through a sulfur (—S—) atom.For example, the term “alkylthio” includes the groups —S—(CH₂)CH₃,—S—CH₂aryl, etc.

[0046] The term “alkylamino” refers to an alkyl, alkenyl, substitutedalkyl or substituted alkenyl group bonded through a nitrogen (—NR′—)group. For example, the term “alkylamino” includes the groups—NR′—C₁₋₁₂alkyl and —NR′—CH₂-aryl, etc. (where R′ is hydrogen, alkyl orsubstituted alkyl as defined above.) When a subscript is used withreference to an alkylamino group, the subscript refers to the totalnumber of carbon atoms attached to the nitrogen atom. Thus, for example,C₁₆alkylamino includes groups such as —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—N(C₁₋₂alkyl)(C₁₋₄alkyl), and so forth. “Amino” refers to the group—NH₂. The term “aminoalkyl” means a substituted alkyl having at leastone amino substituent (e.g., C₁₋₂aminoalkyl includes —CH₂—NH₂,—CH₂—CH₂—NH₂, and —CH(NH₂)CH₃.) “Alkylaminoalkyl” means a substitutedalkyl having at least one alkylamino substituent.

[0047] When a subscript is used as in C₁₋₈alkyl, the subscript refers tothe number of carbon atoms the group may contain. Zero when used in asubscript denotes a bond, e.g., C₀₋₄alkyl refers to a bond or an alkylof 1 to 4 carbon atoms. Thus, for example, “C₁₋₆alkyl” refers tostraight and branched chain alkyl groups with one to six carbon atoms,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl,and so forth. “Hydroxy(C₀₋₂alkyl)” includes hydroxy, hydroxymethyl, andhydroxyethyl. Similarly, “phenyl(C₀₋₂alkyl)” includes phenyl,phenylmethyl, and phenylethyl.

[0048] When used with alkoxy, thioalkyl, or alkylamino (or aminoalkyl),a subscript refers to the number of carbon atoms that the group maycontain in addition to heteroatoms. Thus, for example, monovalentC₁₋₂alkylamino includes the groups —NH—CH₃, —NH—CH₂—CH₃, and —N(CH₃)₂. Alower alkylamino comprises an alkylamino having one to four carbonatoms.

[0049] The alkoxy, alkylthio, or alkylamino groups may be monovalent orbivalent. By “monovalent” it is meant that the group has a valency(i.e., power to combine with another group), of one, and by “bivalent”it is meant that the group has a valency of two. For example, amonovalent alkoxy includes groups such as —O—C₁₋₂alkyl, whereas abivalent alkoxy includes groups such as —O—C₁₋₂alkylene- , etc.

[0050] The term “acyl” refers to a group having a carbonyl

[0051] linked to an organic group i.e.,

[0052] wherein R_(d) may be selected from alkyl, alkenyl, substitutedalkyl, substituted alkenyl, aryl, heterocyclo, cycloalkyl, andheteroaryl, as defined herein.

[0053] The term “alkoxycarbonyl” refers to a group having a carboxy orester group

[0054] linked to an organic radical, i.e.,

[0055] wherein R_(d) is as defined above for acyl.

[0056] The term “carbamyl” refers to a functional group in which anitrogen atom is directly bonded to a carbonyl, i.e., as in—NR_(e)C(═O)R_(f) or —C(═O)NR_(e)R_(f), wherein R_(e) and R_(f) can behydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkoxy, cycloalkyl, aryl, heterocyclo, or heteroaryl, or when attachedto the same nitrogen atom, R_(e) and R_(f) may join to form a ring.

[0057] The term “halo” or “halogen” refers to chloro, bromo, fluoro andiodo.

[0058] The term “haloalkyl” means a substituted alkyl having one or morehalo substituents. For example, “haloalkyl” includes mono, bi, andtrifluoromethyl.

[0059] The term “haloalkoxy” means an alkoxy group having one or morehalo substituents. For example, “haloalkoxy” includes OCF₃.

[0060] The term “sulfonyl” refers to a sulphoxide group (i.e., —S(O)₁₋₂)linked to an organic radical R_(c), as defined above.

[0061] The term “sulfonamidyl” or “sulfonamido” refers to the group—S(O)₂NR_(e)R_(f), wherein R_(e) and R_(f) are as defined above in thedefinition for carbamyl. Preferably when one of R_(e) and R_(f) isoptionally substituted heteroaryl or heterocyclo (as defined below), theother of R_(e) and R_(f) is hydrogen, alkyl, or substituted alkyl.

[0062] The term “cycloalkyl” refers to fully saturated and partiallyunsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7 carbon atoms.The term “cycloalkyl” includes such rings having zero to threesubstituents (preferably 0-2 substituents), selected from 1) R_(g); and2) C₁₋₆ alkyl substituted with one to three R_(g), wherein R_(g) isselected from the group consisting of halogen, alkyl, alkenyl,substituted alkenyl, alkynyl, nitro, cyano, keto (═O), —OR_(a), —SR_(a),—NR_(a)R_(b), —NR_(a)SO₂R_(c), —SO₂R_(c), —SO₂NR_(a)R_(b), —CO₂R_(a),—C(═O)R_(a), —C(═O)NR_(a)R_(b), —OC(═O)R_(a), —OC(═O)NR_(a)R_(b),—NR_(a)C(═O)R_(b), —NR_(a)CO₂R_(b), aryl, heteroaryl, heterocyclo,and/or another 4 to 7 membered cycloalkyl ring, wherein R_(a), R_(b) andR_(c) are defined as above. When R_(a), R_(b) and R_(c) are selectedfrom an alkyl or alkenyl group, such groups are in turn optionallysubstituted as set forth above in the definition for substituted alkyl.The term “cycloalkyl” also includes such rings having a second ringfused thereto (e.g., including benzo, heterocyclo, or heteroaryl rings)or having a carbon-carbon bridge of 3 to 4 carbon atoms. When acycloalkyl has a second ring fused thereto or is substituted with afurther ring, i.e., aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclo, heterocycloalkyl, cycloalkylalkyl, or a further cycloalkylring, such ring in turn may be substituted with one to two C₀₋₆alkylsubstituted with one to two of (or bonded to one of) halogen,tirfluoromethyl, C₂₋₆alkenyl, nitro, cyano, keto (═O), OH, —O(alkyl),phenyloxy, benzyloxy, SH, —S(alkyl), NH₂, —NH(alkyl), —N(alkyl)₂,—NHSO₂(alkyl), —SO₂(alkyl), —SO₂NH₂, —SO₂NH(alkyl), —SO₂N(alkyl)₂,—CO₂H, —CO₂(alkyl), —C(═O)H, —C(═O)alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —OC(═O)alkyl, —OC(═O)NH₂, —OC(═O)NH(alkyl),—NHC(═O)alkyl, and —NHCO₂(alkyl).

[0063] Thus, the term “cycloalkyl” includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., as well as thefollowing ring systems,

[0064] and the like, which optionally may be substituted at anyavailable atoms of the ring(s).

[0065] The term “aryl” refers to phenyl, biphenyl, 1-naphthyl, and2-naphthyl, with phenyl being preferred. The term “aryl” includes suchrings having zero to three substituents (preferably 0-2 substituents),selected from the group consisting of 1) R_(h); and 2) C₁₋₆ alkylsubstituted with one to three R_(g), wherein R_(g) is as defined abovefor cycloalkyl, and R_(h) is selected from the same groups as R_(g) butdoes not include keto (═O). Additionally, two substituents attached toan aryl, particularly a phenyl group, may join to form a further ringsuch as a fused or spiro-ring, e.g., cyclopentyl or cyclohexyl, or fusedheterocyclo or heteroaryl. When an aryl is substituted with a furtherring, such ring in turn may be substituted with one to two C₀₋₆alkylsubstituted with one to two of (or bonded to one of) halogen,tirfluoromethyl, C₂₋₆alkenyl, nitro, cyano, keto (═O), OH, —O(alkyl),phenyloxy, benzyloxy, SH, —S(alkyl), NH₂, —NH(alkyl), —N(alkyl)₂,—NHSO₂(alkyl), —SO₂(alkyl), —SO₂NH₂, —SO₂NH(alkyl), —SO₂N(alkyl)₂,—CO₂H, —CO₂(alkyl), —C(═O)H, —C(═O)alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —OC(═O)alkyl, —OC(═O)NH₂, —OC(═O)NH(alkyl),—NHC(═O)alkyl, and —NHCO₂(alkyl).

[0066] Thus, examples of aryl groups include:

[0067] and the like, which optionally may be substituted at anyavailable carbon or nitrogen atom.

[0068] The term “heterocyclo” or “heterocyclic” refers to substitutedand unsubstituted non-aromatic 3 to 7 membered monocyclic groups, 7 to11 membered bicyclic groups, and 10 to 15 membered tricyclic groups, inwhich at least one of the rings has at least one heteroatom (O, S or N).Each ring of the heterocyclo group containing a heteroatom can containone or two oxygen or sulfur atoms and/or from one to four nitrogen atomsprovided that the total number of heteroatoms in each ring is four orless, and further provided that the ring contains at least one carbonatom. The fused rings completing bicyclic and tricyclic groups maycontain only carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. The heterocyclogroup may be attached at any available nitrogen or carbon atom. Theheterocyclic ring may contain zero to three substituents (preferably 0-2substituents), selected from 1) R_(g); and 2) C₁₋₆ alkyl substitutedwith one to three R_(g), wherein R_(g) is defined as above forcycloalkyl groups. Additionally, when a heterocyclo is substituted witha further ring, such ring in turn may be substituted with one to twoC₀₋₆alkyl substituted with one to two of (or bonded to one of) halogen,tirfluoromethyl, C₂₋₆alkenyl, nitro, cyano, keto (═O), OH, —O(alkyl),phenyloxy, benzyloxy, SH, —S(alkyl), NH₂, —NH(alkyl), —N(alkyl)₂,—NHSO₂(alkyl), —SO₂(alkyl), —SO₂NH₂, —SO₂NH(alkyl), —SO₂N(alkyl)₂,—CO₂H, —CO₂(alkyl), —C(═O)H, —C(═O)alkyl, —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)₂, —OC(═O)alkyl, —OC(═O)NH₂, —OC(═O)NH(alkyl),—NHC(═O)alkyl, and —NHCO₂(alkyl).

[0069] Thus, exemplary heterocyclic groups include, without limitation:

[0070] and the like, which optionally may be substituted at anyavailable carbon or nitrogen atom.

[0071] The term “heteroaryl” refers to substituted and unsubstitutedaromatic 5 to 7 membered monocyclic groups, 9 or 10 membered bicyclicgroups, and 11 to 14 membered tricyclic groups which have at least oneheteroatom (O, S or N) in at least one of the rings. Each ring of theheteroaryl group containing a heteroatom can contain one or two oxygenor sulfur atoms and/or from one to four nitrogen atoms provided that thetotal number of heteroatoms in each ring is four or less and each ringhas at least one carbon atom. The fused rings completing the bicyclicand tricyclic groups may contain only carbon atoms and may be saturated,partially saturated, or unsaturated. The nitrogen and sulfur atoms mayoptionally be oxidized and the nitrogen atoms may optionally bequaternized. Heteroaryl groups which are bicyclic or tricyclic mustinclude at least one fully aromatic ring but the other fused ring orrings may be aromatic or non-aromatic. The heteroaryl group may beattached at any available nitrogen or carbon atom of any ring. Theheteroaryl ring system may contain zero to three substituents(preferably 0-2 substituents), selected from 1) R_(h); and 2) C₁₋₆ alkylsubstituted with one to three R_(g), wherein R_(g) and R_(h) are definedabove as for aryl groups. Additionally, when a heteroaryl is substitutedwith a further ring, such ring in turn may be substituted with one totwo C₀₋₆alkyl substituted with one to two of (or bonded to one of)halogen, tirfluoromethyl, C₂₋₆alkenyl, nitro, cyano, keto (═O), OH,—O(alkyl), phenyloxy, benzyloxy, SH, —S(alkyl), NH₂, —NH(alkyl),—N(alkyl)₂, —NHSO₂(alkyl), —SO₂(alkyl), —SO₂NH₂, —SO₂NH(alkyl),—SO₂N(alkyl)₂, —CO₂H, —CO₂(alkyl), —C(═O)H, —C(═O)alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —OC(═O)alkyl, —OC(═O)NH₂,—OC(═O)NH(alkyl), —NHC(═O)alkyl, and —NHCO₂(alkyl).

[0072] Examples of heteroaryl rings include

[0073] and the like, which optionally may be substituted at anyavailable carbon or nitrogen atom.

[0074] The term “carbocyclic” refers to optionally substituted aromaticor non-aromatic 3 to 7 membered monocyclic and 7 to 11 membered bicyclicgroups, in which all atoms of the ring or rings are carbon atoms. Acarbocyclic ring system may optionally be substituted as defined abovefor aryl and cycloalkyl groups.

[0075] When the term “unsaturated” is used herein to refer to a ring orgroup, the ring or group may be fully unsaturated or partiallyunsaturated.

[0076] When reference is made to a specifically -named ringed group,such as cyclohexyl, phenyl, morpholinyl, oxazolyl, and the like, itshould be understood that, unless the presence or absence ofsubstituents is otherwise specifically stated, these groups optionallymay be substituted as recited above for the corresponding genus of ringsin which they belong.

[0077] When reference is made generally to a monocyclic or bicyclic ringsystem, such reference is intended to include cycloalkyl, aryl,heterocyclo, and heteroaryl rings, as defined above.

[0078] The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

[0079] Whenever a bond appears in a formula as a dashed-double bond,i.e., with one bond appearing as a dash as in

[0080] it should be understood that such bonds may be selected fromsingle or double bonds, as appropriate given the selections for adjacentatoms and bonds.

[0081] Multiple substituents may be selected for any compound within thescope of this invention; however, advantageously substituents areselected so that the compounds of formula (I) have a molecular weight ofless than 1,500. More preferred are compounds having a molecular weightof less than 1,000, and even more preferred are compounds having amolecular of less than 500.

[0082] It should be understood that one skilled in the field may makevarious substitutions for each of the groups recited in the claimsherein, without departing from the spirit or scope of the invention.

[0083] Throughout the specification, groups and substituents thereof maybe chosen by one skilled in the field to provide stable moieties andcompounds.

[0084] The compounds of the present invention form salts which are alsowithin the scope of this invention. Unless otherwise indicated,reference to an inventive compound is understood to include reference tosalts thereof. The term “salt(s)” denotes acidic and/or basic saltsformed with inorganic and/or organic acids and bases. In addition, theterm “salt(s) may include zwitterions (inner salts), e.g., when acompound of the present invention contains both a basic moiety, such asan amine or a pyridine or imidazole ring, and an acidic moiety, such asa carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, such as, for example,acceptable metal and amine salts in which the cation does not contributesignificantly to the toxicity or biological activity of the salt.However, other salts may be useful, e.g., in isolation or purificationsteps which may be employed during preparation, and thus, arecontemplated within the scope of the invention. Salts of the compoundsof the present invention may be formed, for example, by reacting acompound of the present invention with an amount of acid or base, suchas an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

[0085] Exemplary acid addition salts include acetates (such as thoseformed with acetic acid or trihaloacetic acid, for example,trifluoroacetic acid), adipates, alginates, ascorbates, aspartates,benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

[0086] Exemplary basic salts include ammonium salts, alkali metal saltssuch as sodium, lithium, and potassium salts; alkaline earth metal saltssuch as calcium and magnesium salts; barium, zinc, and aluminum salts;salts with organic bases (for example, organic amines) such astrialkylamines such as triethylamine, procaine, dibenzylamine,N-benzyl-β-phenethylamine, 1-ephenamine, N,N′-dibenzylethylene-diamine,dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamineor similar pharmaceutically acceptable amines and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quaternized with agents such as lower alkyl halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others. Preferred salts includemonohydrochloride, hydrogensulfate, methanesulfonate, phosphate ornitrate.

[0087] Prodrugs and solvates of the inventive compounds are alsocontemplated. The term “prodrug” denotes a compound which, uponadministration to a subject, undergoes chemical conversion by metabolicor chemical processes to yield a compound of the present invention,and/or a salt and/or solvate thereof. Various forms of prodrugs are wellknown in the art. For examples of such prodrug derivatives, see:

[0088] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985)and Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, etal. (Acamedic Press, 1985);

[0089] b) A Textbook of Drug Design and Development, edited byKrosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application ofProdrugs,” by H. Bundgaard, 113-191 (1991); and

[0090] c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992),each of which is incorporated herein by reference.

[0091] Compounds containing a carboxy group can form physiologicallyhydrolyzable esters which serve as prodrugs by being hydrolyzed in thebody to yield the present invention compounds per se. Such prodrugs arepreferably administered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of the presentinvention include C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g. acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl,C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g. methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

[0092] Compounds of the present invention or salts thereof may exist intheir tautomeric form, in which hydrogen atoms are transposed to otherparts of the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that theall tautomeric forms, insofar as they may exist, are included within theinvention. Additionally, inventive compounds may have trans and cisisomers and may contain one or more chiral centers, therefore existingin enantiomeric and diastereomeric forms. The invention includes allsuch isomers, as well as mixtures of cis and trans isomers, mixtures ofdiastereomers and racemic mixtures of enantiomers (optical isomers).When no specific mention is made of the configuration (cis, trans or Ror S) of a compound (or of an asymmetric carbon), then any one of theisomers or a mixture of more than one isomer is intended. The processesfor preparation can use racemates, enantiomers or diastereomers asstarting materials. When enantiomeric or diastereomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

[0093] The compounds of the instant invention may, for example, be inthe free or hydrate form, and may be obtained by methods exemplified bythe following descriptions.

[0094] Preferred Compounds

[0095] The methods of the invention preferably comprise administrationof compounds of formula (I),

[0096] or pharmaceutically-acceptable salts, hydrates, and prodrugsthereof, in which:

[0097] A is selected from phenyl, oxazolyl, thiazolyl, isothiazolyl,imidazolyl, furyl, thienyl, thiadiazolyl, oxadiazolyl, tetrazolyl,triazolyl, diazoly, pyrrolyl, and pyrazolyl, said ring A beingoptionally substituted with up to two groups selected from halogen,C₁₋₄alkyl, haloalkyl, haloalkoxy, OH, C₁₋₄alkoxy, C₁₋₄alkylcarbonyl, CN,NH₂, NH(C₁₋₄alkyl), and N(alkyl)_(2;)

[0098] B is

[0099] D is phenyl, or A is a carbocyclic ring and D is selected frompyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiophenyl, andpyrrolyl;

[0100] R₁ is selected from hydrogen, C₁₋₄alkyl, and C₁₋₄alkylsubstituted with one of halogen, hydroxy, amino, C₁₋₃alkoxy, orC₁₋₆alkylamino;

[0101] R₂ and R₃ are attached to any available carbon atom of ring B andring D, respectively, and at each occurrence are independently selectedfrom halogen, cyano, C₁₋₄alkyl, hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl),OCF₃(C₀₋₄alkyl), cyano(C₁₋₄alkyl), amino(C₀₋₄alkyl),C₁₋₄alkoxy(C₀₋₄alkyl), C₁₋₆alkylamino(C₀₋₄alkyl), andC₁₋₄alkylthio(C₀₋₄alkyl);

[0102] R₄, R₅, R₆, R₇ and R₈ are independently selected from hydrogenand C₁₋₄alkyl;

[0103] R₉ and R₁₀ are independently selected from hydrogen, C₁₋₄alkyl,and C₁₋₄alkyl substituted with one to two R₂₅; or alternatively, R₉ andR₁₀ taken together may form a 3-8 membered heterocyclic ring or a fiveto six membered heteroaryl ring, said ring being optionally substitutedwith up to three R₃₀;

[0104] R₁₁ at each occurrence is independently selected from halogen,cyano, C₁₋₄alkyl, hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl),cyano(C₁₋₄ alkyl), amino(C₀₋₄alkyl), C₁₋₄alkoxy(C₀₋₄alkyl),C₁₋₆alkylamino(C₀₋₄alkyl), and C₁₋₄alkylthio(C₀₋₄alkyl), or two R₁₁groups may be taken together to form a fused benzo, heteroaryl, orheterocyclic ring, wherein said ring in turn is optionally substitutedwith up to one A group and/or one to two of hydrogen, halogen,C₁₋₄alkyl, hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl),cyano(C₀₋₄alkyl), and C₁₋₄alkoxy(C₀₋₄alkyl);

[0105] R₂₅ is halogen, hydroxy, C₁₋₃alkoxy, amino, or C₁₋₆alkylamino;

[0106] R₃₀ is selected from C₁₋₄alkyl, oxo (═O), halo(C₀₋₄alkyl),hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl), cyano(C₀₋₄alkyl),amino(C₀₋₄alkyl), C₁₋₄alkoxy(C₀₋₄alkyl), C₁₋₆alkylamino(C₀₋₄alkyl),C₁₋₄alkylthio(C₀₋₄alkyl), —C(═O)C₁₋₄alkyl, and —CO₂C₁₋₄alkyl;

[0107] a is 0 or 1;

[0108] m is 0, 1, or 2;

[0109] n is 0, 1, 2, 3, or 4;

[0110] p is 0, 1 or 2; and

[0111] q is 0, 1, 2, 3 or 4.

[0112] The methods of the invention preferably comprise administrationof compounds of formula (I), where A is selected from phenyl, oxazolyl,thiazolyl, isothiazolyl, imidazolyl, furyl, thienyl, thiadiazolyl,oxadiazolyl, tetrazolyl, triazolyl, diazolyl, pyrrolyl, and pyrazolyl,said ring A being optionally substituted with up to two groups selectedfrom halogen, C₁₋₄alkyl, trifluoromethyl, or cyano. More preferably A isoxazolyl which is unsubstituted or substituted with C₁₋₂alkyl, and D iscarbocyclic.

[0113] The methods of the invention preferably comprise administrationof compounds of formula (I), where B is

[0114] more preferably B is

[0115] and even more preferred are compounds where B is

[0116] and is unsubstituted. Thus, R₂ is preferably absent (or R_(2a) ispreferably hydrogen).

[0117] The methods of the invention preferably comprise administrationof compounds of formula (I), where D is selected from phenyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiophenyl, and pyrrolyl;more preferred are compounds where D is phenyl.

[0118] The methods of the invention preferably comprise administrationof compounds of formula (I), where R₃ is absent, or is attached to anyavailable carbon atom of ring D and at each occurrence is independentlyselected from halogen, cyano, C₁₋₄alkyl, hydroxy(C₀₋₄alkyl),CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl), cyano(C₁₋₄alkyl), amino(C₀₋₄alkyl),C₁₋₄alkoxy(C₀₋₄alkyl), C₁₋₆alkylamino(C₀₋₄alkyl), andC₁₋₄alkylthio(C₀₋₄alkyl). More preferred are methods comprising use ofcompounds where R₃ is absent or if present, is halogen, more preferablyfluoro, wherein n is 1-4.

[0119] In the methods of the invention, preferably R₆ is selected fromC₁₋₄alkyl; more preferably methyl.

[0120] The methods of the invention preferably comprise administrationof compounds of formula (I), where R₄, R₅, R₇, R₈, R₉ and R₁₀ are eachselected from hydrogen and C₁₋₄alkyl; more preferably each of saidgroups is hydrogen.

[0121] The methods of the invention preferably comprise administrationof compounds of formula (I), where R₁₁ is selected from halogen, cyano,C₁₋₄alkyl, CF₃, OCF₃ and C₁₋₄alkoxy, and q is 0 or 1.

[0122] Also preferred in practicing the methods of the invention arecompounds having the formula (Ia),

[0123] or pharmaceutically-acceptable salts, hydrates, or prodrugsthereof, in which:

[0124] A is selected from phenyl, oxazolyl, thiazolyl, isothiazolyl,imidazolyl, furyl, thienyl, thiadiazolyl, oxadiazolyl, tetrazolyl,triazolyl, diazolyl, pyrrolyl, and pyrazolyl, said ring A beingoptionally substituted with up to two groups selected from halogen, NO₂,C₁₋₄alkyl, haloalkyl, haloalkoxy, OH, C₁₋₄alkoxy, C₁₋₄alkylcarbonyl, CN,NH₂, NH(C₁₋₄alkyl), and N(alkyl)₂;

[0125] D is phenyl, or when A is phenyl, then D is selected frompyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thiophenyl, andpyrrolyl;

[0126] R_(2a) is selected from hydrogen, halogen, and C₁₋₄alkyl;

[0127] R₃ is selected from halogen, C₁₋₄alkyl, CF₃, OCF₃, cyano, andC₁₋₃alkoxy;

[0128] R₆ is C₁₋₄alkyl;

[0129] R₁₁, is selected from hydrogen, halogen, C₁₋₄alkyl,hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl), cyano(C₀₋₄alkyl),amino(C₀₋₄alkyl), C₁₋₃alkoxy(C₀₋₄alkyl), and C₁₋₆alkylamino(C₀₋₄alkyl),or two R₁₁ groups may be taken together to form a fused benzo,heteroaryl, or heterocyclic ring, wherein said ring in turn isoptionally substituted with up to one A group and/or one to two ofhydrogen, halogen, C₁₋₄alkyl, hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl),OCF₃(C₀₋₄alkyl), cyano(C₀₋₄alkyl), and C₁₋₄alkoxy(C₀₋₄alkyl);

[0130] R₉ and R₁₀ are independently selected from hydrogen andC₁₋₄alkyl;

[0131] a is 0 or 1;

[0132] n is 0, 1, 2, 3, or 4;

[0133] p is 0, 1 or 2; and

[0134] q is 0, 1, or 2.

[0135] Most preferred are the inventive methods comprisingadministration of the compounds as immediately defined above, wherein Ais oxazolyl that is unsubstituted or substituted with C₁₋₂alkyl; D isphenyl; R_(2a) is hydrogen; R₃ is absent (n is 0), or R₃ is halogen,more preferably fluoro (and n is 1-4); R₆ is methyl; R₁₁ is hydrogen,halogen, or methoxy; R₉ and R₁₀ are hydrogen; a is 0 or 1; and p is 1.

[0136] The invention also relates to preferred compounds of the presentinvention, exemplified herein and as defined above, which havedemonstrated activity in inhibiting Factor VIIa with IC₅₀ values(concentration required to inhibit 50% of specific binding) below 1 μM,and more preferred compounds that have demonstrated IC₅₀ values of below500 nM.

[0137] Methods of Preparation

[0138] The compounds of the present invention may be synthesized usingconventional techniques known in the art. Advantageously, thesecompounds are conveniently synthesized from readily-available startingmaterials. Additionally, illustrative general synthetic schemes formaking compounds of the present invention are set forth below, andmethods for making the compounds useful to the invention are also setforth in the Examples that follow hereinafter. In these schemes, thegroup Q may designate the substituent R₁₁ or an appropriate precursorthereto, which one skilled in the field may select as appropriate for agiven reaction. Groups designated A, D, etc., are also intended to referto such groups as recited in the claims.

[0139] The preparation of heterocycles useful to this invention isdescribed in the literature, e.g., Katritzky et al., “ComprehensiveHeterocyclic Chemistry, The Structure, Reactions, Synthesis and Uses ofHeterocyclic Compounds,” (Pergamon Press New York, 1984 [1st Ed.], and1996). Methods of preparation useful to make compounds of this inventionalso may be described in U.S. Pat. No. 6,399,773, which is incorporatedherein by reference.

[0140] Reaction of an appropriately-substituted amine (1) with a reagentsuch as 1,1′-thiocarbonyldi-2(1H)-pyridone, 1,1′-thiocarbonyldiimidazoleor thiophosgene in a solvent such as methylene chloride or dioxaneyields the isothiocyanate (2). Treatment of the isothiocyanate (2) withsodium salt of cyanamide yields the sodium salt of N-cyanothiourea (3),which is cyclized to the substituted 1,2,4-aminotriazole (II), using anappropriately-substituted hydrazine and a dehydrating agent such as EDCor DCC.

[0141] An appropriately-substituted amine (1) can be reacted withdiphenyl cyanocarbonimidate to yield the N-cyano-O-phenylisourea (4).Cyclization of compound (4) to the substituted triazole (II) is achievedusing an appropriately-substituted hydrazine and a solvent such asacetonitrile.

[0142] Reaction of an isothiocyanate (2) with a β-ketoamine in thepresence of a base such as TEA and a solvent such as dioxane yields thethiourea (5). Reaction of the thiourea in the presence of a dehydratingagent such as dicyclohexylcarbodiimide or EDC, in a solvent such asdioxane or toluene, at a temperature preferably between 60° C. and 110°C., yields the desired 2-aminooxazoles (III). β-ketoamines are eithercommercially available or can be readily prepared by several methods.One exemplary method is reduction of azidoketones of the type describedin schemes 5a-5d, by phosphine reagents such as triphenylphosphine in asolvent such as dioxane, followed by the addition of water or diluteammonium hydroxide.

[0143] Reaction of an appropriately-substituted isothiocyanate (2) withan acylazide of the type described in schemes 5a-5b in the presence of aphosphine such as triphenyphosphine in a solvent such as DCM or dioxaneat a temperature from rt to 100° C., also yields compounds (III). Oneskilled in the field will recognize that caution should be exercisedwhile handling organic azides.

[0144] Treatment of the α-bromoketone (6) with sodium azide in a solventsuch as acetone, generally at rt, yields the desired α-azidoketones (7)useful as intermediates in this invention. α-Bromoketones (6) arecommercially available. Alternatively, α-bromoketones can be readilyprepared from a ketone [CH₃—C(═O)D], by (a) reaction with a brominatingagent such as bromine in acetic acid or pyridinium bromide perbromideand 30% hydrobromic acid; (b) reaction with a carboxylic acid,iso-butylchloroformate and N-methylmorpholine to provide the mixedanhydride, which on treatment with diazomethane (CH₂N₂) gives theα-diazoketone. Reaction of the α-diazoketone with either HBr gas in asolvent such as ether or dioxane, or aqueous 48% HBr, provides theαbromoketone (6); or (c) reaction with sulfuric acid and bromine whichyields the α,α,-dibromoketone, which on treatment with diethylphosphiteand TEA yields the α-(mono)bromoketone (6).

[0145] Reaction of an aryl bromide (8) with tributyl(1-ethoxyvinyl) tinand bis-(triphenylphosphine)palladium dichloride provides anintermediate enol ether. Treatment of the enol ether withN-bromosuccinamide at a temperature from 0° C. to rt yields theα-bromoketone (9). As described in Scheme 5a, treatment of theαbromoketone with sodium azide in acetone gives the α-azidoketone (10).

[0146] Aryl boronic acids and esters of type (12), may be prepared fromthe corresponding arylbromide (11) by treatment with a palladiumcatalyst such as [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II) and bis(pinacolato)diboron, as reported byIshayama et al., J. Org. Chem., 1995, 7508-7510. Aryl boronic esters maybe converted to the corresponding boronic acids by several methodsincluding treatment with aqueous HCl. In a variation of the synthesis,the nitrogen may be masked as a nitro group and later reduced by severalmeans including metal reductions, such as by treatment with tin chloridein HCl or by refluxing the nitro compound with zinc in the presence ofCaCl₂ in a solvent such as EtOH, or in certain cases the nitro group maybe reduced by catalytic hydrogenation in the presence of catalysts suchas Pd/C. The conditions for the reduction of nitro groups are detailedin several references including Hudlicky, M., “Reductions in OrganicChemistry”, 2nd Ed., ACS Monograph 188 (1996), pp.91-101. In a secondvariation of the synthesis, the aryl bromide is allowed to remainthrough the entire synthesis and elaborated to the boronic acid at theend. This may eliminate the need for a protecting group.

[0147] Suzuki-type cross coupling of an aryl boronic acid or ester (12)with an appropriate bromoheterocycle (13) in the presence of a suitablecatalyst such as Pd(PPh₃)₄ yields the desired protected amide (14) (see,e.g., Miyaura et al., Synth. Comm., 1981, 11(7), 513-19; Suzuki et al.,J. Am. Chem. Soc. 1989, 111:513; and Kalinin, Russ. Chem. Rev., 1991,60, 173). The amide (13) may be deprotected as known to one skilled inthe art (see, e.g., Greene and Wuts, Protective Groups in OrganicSynthesis, (John Wiley and Sons, Inc., New York, N.Y. 1991). Forexample, if the protecting group is acetyl, the product may bedeprotected by treatment with aqueous KOH at a concentration of 0.5 N to5 N at rt to 100° C for a period between 0.5 h and 24 h, to provideamine (14), an intermediate for making compounds according to theinvention. Compounds (12) can be prepared as shown in Scheme 6.

[0148] Aryl boronic acid (12) may be reacted with 5-bromothiazole in thepresence of Pd(PPh₃)₄, to provide (15). Alternatively, aryl boronic acid(12) may be reacted with oxazolone in the presence of copper (II)acetate and an amine base such as pyridine to provide intermediate (16).Compounds (15) and (16) may be deprotected by an appropriate method.Copper has been shown to be an effective catalyst for cross coupling ofaryl boronic acids to N-unsubstituted heterocycles as described by Chan.et al., Tetrahed. Lett., 1998, 39, 2933-36; and Lam et al., Tetrahed.Lett., 1998, 39,2941 -44. This results in compounds in which theheterocycle is attached to the aryl ring through nitrogen rather thancarbon.

[0149] Oxazoles may be prepared by 1,3 dipolar cycloaddition of thecorresponding aldehyde (17) and (p-tolylsulfonyl)methyl isocyanate(TOSMIC) (19). The aldehyde may be commercially available or preparedfrom the corresponding methyl group by oxidation with reagents such asCrO₃, MnO₂, and ammonium cerium (IV) nitrate. These methods are wellknown to one skilled in the art and described in Hudlicky, M.,Oxidations in Organic Chemistry, ACS Monograph 186 (1990). The nitrogroup in intermediate (19) is reduced to an amine (20) by methods knownin the field. Synthesis of 5-membered heterocycles by 1,3-dipolarcycloaddition is also described by Padwa, 1,3-Dipolar CycloadditionChemistry, Vols. 1 & 2 (John Wiley and Sons, New York, N.Y., 1984).

[0150] Halonitrobenzenes (21) are either commercially available or canbe readily prepared by methods known to one skilled in the art.Displacement of halonitrobenzenes (21) with a variety of nucleophilesproduces compounds of structure (22). In one example, heating (21 a)with a nucleophilic heterocycle such as triazole with or without theaddition of a base provides the intermediate nitro compound which may bereduced as previously described to provide amines (22a). Alternatively,simple organic nucleophiles such as cyanide can be reacted withhalonitrobenzene (21b) to provide an intermediate nitrocompound whichcan be reduced by many methods to produce amine (22b).

[0151] Utility

[0152] The inventive compounds are inhibitors of the serine proteaseFVIIa. Thus, the compounds are useful for treating or preventing thoseprocesses, which involve the action of Factor VIIa. As used herein withreference to the utilities described below, the term “treating” or“treatment” encompasses either or both responsive and prophylaxismeasures, e.g., measures designed to inhibit or delay the onset of thedisease or disorder, achieve a full or partial reduction of the symptomsor disease state, and/or to alleviate, ameliorate, lessen, or cure thedisease or disorder and/or its symptoms.

[0153] In view of their above-referenced FVIIa inhibitory activity, theinventive compounds are useful in treating consequences ofatherosclerotic plaque rupture including cardiovascular diseasesassociated with the activation of the coagulation cascade in thromboticor thrombophilic states. Such diseases include arterial thrombosis,coronary artery disease, acute coronary syndromes, myocardialinfarction, unstable angina, ischemia resulting from vascular occlusioncerebral infarction, stroke and related cerebral vascular diseases(including cerebrovascular accident and transient ischemic attack).Additionally, the compounds are useful in treating or preventingformation of atherosclerotic plaques, transplant atherosclerosis,peripheral arterial disease and intermittent claudication. In addition,the compounds can be used to prevent restenosis following arterialinjury induced endogenously (by rupture of an atherosclerotic plaque),or exogenously (by invasive cardiological procedures such as vessel wallinjury resulting from angioplasty).

[0154] In addition, the inventive compounds are useful in preventingvenous thrombosis, coagulation syndromes, deep vein thrombosis (DVT),disseminated intravascular coagulopathy, Kasabach-Merritt syndrome,pulmonary embolism, cerebral thrombosis, atrial fibrillation, andcerebral embolism. The compounds are useful in treating peripheralarterial occlusion, thromboembolic complications of surgery (such as hipreplacement, endarterectomy, introduction of artificial heart valves,vascular grafts, and mechanical organs), implantation or transplantationof organ, tissue or cells, and thromboembolic complications ofmedications (such as oral contraceptives, hormone replacement, andheparin, e.g., for treating heparin-induced thrombocytopenia). Theinventive compounds are useful in preventing thrombosis associated withartificial heart valves, stents, and ventricular enlargement includingdilated cardiac myopathy and heart failure. The compounds are alsouseful in treating thrombosis due to confinement (i.e. immobilization,hospitalization, bed rest etc.).

[0155] These compounds are also useful in preventing thrombosis andcomplications in patients genetically predisposed to arterial thrombosisor venous thrombosis (including activated protein C resistance,FV_(leiden), Prothrombin 20210, elevated coagulation factors FVII,FVIII, FIX, FX, FXI, prothrombin, TAFI and fibrinogen), elevated levelsof homocystine, and deficient levels of antithrombin, protein C, andprotein S. The inventive compounds may be used for treatingheparin-intolerant patients, including those with congenital andacquired antithrombin III deficiencies, heparin-inducedthrombocytopenia, and those with high levels of polymorphonucleargranulocyte elastase.

[0156] The present compounds may also be used to inhibit bloodcoagulation in connection with the preparation, storage, fractionation,or use of whole blood. For example, the compounds may be used tomaintain whole and fractionated blood in the fluid phase such asrequired for analytical and biological testing, e.g., for ex vivoplatelet and other cell function studies, bioanalytical procedures, andquantitation of blood-containing components. The compounds may be usedas anticoagulants in extracorpeal blood circuits, such as thosenecessary in dialysis and surgery (such as coronary artery bypasssurgery); for maintaining blood vessel patency in patients undergoingtransluminal coronary angioplasty, vascular surgery including bypassgrafting, arterial reconstruction, atherectomy, vascular graft and stentpatency, tumor cell metastasis, and organ, tissue, or cell implantationand transplantation.

[0157] In addition, the compounds of the present invention may be usefulin treating cancer and preventing the prothrombotic complications ofcancer. The compounds may be useful in treating tumor growth, as anadjunct to chemotherapy, for preventing angiogenesis, and for treatingcancer, more particularly, cancer of the lung, prostate, colon, breast,ovaries, and bone.

[0158] The inventive compounds may also be used in combination withother antithrombotic or anticoagulant drugs such as thrombin inhibitors,platelet aggregation inhibitors such as aspirin, clopidogrel,ticlopidine or CS-747, warfarin, low molecular weight heparins (such asLOVENOX), GPIIb/GPIIIa blockers, PAI-1 inhibitors such as XR-330 andT-686, inhibitors of α-2-antiplasmin such as anti-α-2-antiplasminantibody and thromboxane receptor antagonists (such as ifetroban),prostacyclin mimetics, phosphodiesterase (PDE) inhibitors, such asdipyridamole or cilostazol, PDE inhibitors in combination withthromboxane receptor antagonists/thromboxane A synthetase inhibitors(such as picotamide), serotonin-2-receptor antagonists (such asketanserin), fibrinogen receptor antagonists, hypolipidemic agents, suchas HMG-CoA reductase inhibitors, e.g., pravastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, AZ4522, itavastatin(Nissan/Kowa), and compounds disclosed in U.S. provisional applicationsNo. 60/211,594 filed Jun. 15, 2000, and No. 60/211,595 filed Jun. 15,2000; microsomal triglyceride transport protein inhibitors (such asdisclosed in U.S. Pat. Nos. 5,739,135, 5,712,279 and 5,760,246),antihypertensive agents such as angiotensin-converting enzyme inhibitors(e.g., captopril, lisinopril or fosinopril); angiotensin-II receptorantagonists (e.g., irbesartan, losartan or valsartan); and/or ACE/NEPinhibitors (e.g., omapatrilat and gemopatrilat); β-blockers (such aspropranolol, nadolol and carvedilol), PDE inhibitors in combination withaspirin, ifetroban, picotamide, ketanserin, or clopidogrel and the like.The inventive compounds are also useful in combination withanti-arrhythmic agents such as for atrial fibrillation, for example,amiodarone or dofetilide.

[0159] The inventive compounds may be used in combination withprothrombolytic agents, such as tissue plasminogen activator (natural orrecombinant), streptokinase, reteplase, activase, lanoteplase,urokinase, prourokinase, anisolated streptokinase plasminogen activatorcomplex (ASPAC), animal salivary gland plasminogen activators, and thelike.

[0160] The inventive compounds may also be used in combination withβadrenergic agonists such as albuterol, terbutaline, formoterol,salmeterol, bitolterol, pilbuterol, or fenoterol; anticholinergics suchas ipratropium bromide; anti-inflammatory cortiocosteroids such asbeclomethasone, triamcinolone, budesonide, fluticasone, flunisolide ordexamethasone; and anti-inflammatory agents such as cromolyn,nedocromil, theophylline, zileuton, zafirlukast, monteleukast andpranleukast.

[0161] The inventive compounds may also be useful in combination withother anticancer strategies and chemotherapies such as taxol and/orcisplatin.

[0162] The compounds may act synergistically with one or more of theabove agents. For example, the inventive compounds may actsynergistically with the above agents to prevent reocclusion following asuccessful thrombolytic therapy and/or reduce the time to reperfusion.Thus, reduced doses of thrombolytic agent(s) may be used, thereforeminimizing potential hemorrhagic side effects.

[0163] The compounds of the present invention may be administered by anymeans suitable for the condition to be treated, which may depend on theneed for site-specific treatment or quantity of drug to be delivered.Systematic treatment is typically preferred for cancerous conditions,although other modes of delivery are contemplated. The compounds may bedelivered orally, such as in the form of tablets, capsules, granules,powders, or liquid formulations including syrups; sublingually; bucally;transdermally; parenterally, such as by subcutaneous, intravenous,intramuscular or intrasternal injection or infusion (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasallysuch as by inhalation spray; rectally such as in the form ofsuppositories, or in the form of liposome particles. Dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents may be administered. The compounds may be administered in aform suitable for immediate release or extended release. Immediaterelease or extended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps.

[0164] Exemplary compositions for oral administration includesuspensions which may contain, for example, microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners orflavoring agents such as those known in the art; and immediate releasetablets which may contain, for example, microcrystalline cellulose,dicalcium phosphate, starch, magnesium stearate and/or lactose and/orother excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. The inventive compounds maybe orally delivered by sublingual and/or buccal administration, e.g.,with molded, compressed, or freeze-dried tablets. Exemplary compositionsmay include fast-dissolving diluents such as mannitol, lactose, sucrose,and/or cyclodextrins. Also included in such formulations may be highmolecular weight excipients such as celluloses (AVICEL®) or polyethyleneglycols (PEG); an excipient to aid mucosal adhesion such ashydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC),sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer(e.g., GANTREZ®); and agents to control release such as polyacryliccopolymer (e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloringagents and stabilizers may also be added for ease of fabrication anduse.

[0165] Exemplary compositions for nasal aerosol or inhalationadministration include solutions which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhanceabsorption and/or bioavailability, and/or other solubilizing ordispersing agents such as those known in the art.

[0166] Exemplary compositions for parenteral administration includeinjectable solutions or suspensions which may contain, for example,suitable non-toxic, parenterally acceptable diluents or solvents, suchas mannitol, 1,3-butanediol, water, Ringer's solution, an isotonicsodium chloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

[0167] Exemplary compositions for rectal administration includesuppositories which may contain, for example, suitable non-irritatingexcipients, such as cocoa butter, synthetic glyceride esters orpolyethylene glycols, which are solid at ordinary temperatures butliquefy and/or dissolve in the rectal cavity to release the drug.

[0168] The effective amount of a compound of the present invention maybe determined by one of ordinary skill in the art. The specific doselevel and frequency of dosage for any particular subject may vary andwill depend upon a variety of factors, including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.An exemplary effective amount of compounds of the present invention maybe within the dosage range of about 0.1 to about 100 mg/kg, preferablyabout 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25mg/kg (or from about 1 to about 2500 mg, preferably from about 5 toabout 2000 mg) on a regimen in single or 2 to 4 divided daily doses.

[0169] Factor VIIa Assay

[0170] Compound was prepared as a 5 mM stock in DMSO, diluted further inDMSO and added directly to the assays. The DMSO concentration for allthese studies was less than 1% and compared to DMSO vehicle controls.

[0171] Human Factor VIIa was obtained from Enzyme Research Labs (Cat.#HFVIIA 1640). Human recombinant tissue factor (INNOVIN from Dade BehringCat.# B4212-100; “20 ml vial”) was diluted with 8 ml of H₂O per vial anddiluted further 1:30 into the 302 μl final assay volume. Tissue factoractivated FVIIa enzymatic activity was measured in a buffer containing150 mM NaCl, 5 mM CaCl₂, 1 mM CHAPS and 1 mg/ml PEG 6000 (pH 7.4) with 1nM FVIIa and 100 μM D-Ile-Pro-Arg-AFC (Enzyme Systems Products, Km>200μM) 0.66% DMSO. The assay (302 μl total volume) was incubated at RT for2 hr prior to reading fluorometric signal (Ex 405 /Em 535) using aVictor 2 (Wallac) fluorescent plate reader.

[0172] To determine the compound concentration that inhibited half ofthe enzyme activity (IC₅₀), the fraction of control activity (FCA) wasplotted as a function of the inhibitor concentration and curve to fitFCA/(1 [I]/IC₅₀). The IC₅₀ for each compound was determined 2-4 timesand the obtained values were averaged.

[0173] Applying the above-described assays, the inventive compoundsdemonstrated activity as inhibitors of Factors VIIa.

[0174] The following Examples illustrate embodiments of the inventivecompounds and starting materials, and are not intended to limit thescope of the claims. For ease of reference, the following abbreviationsare used herein:

[0175] Abbreviations

[0176] Me=methyl

[0177] Et=ethyl

[0178] Ph=phenyl

[0179] Bn=benzyl

[0180] t-Bu=tertiary butyl

[0181] Boc=tert-butoxycarbonyl

[0182] CBZ=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl

[0183] THF=tetrahydrofuran

[0184] EtOAc=ethyl acetate

[0185] DMF=dimethyl formamide

[0186] i-PrOH=isopropanol

[0187] DMSO=dimethyl sulfoxide

[0188] DME=1,2 dimethoxyethane

[0189] DCE=1,2 dichloroethane

[0190] DCM=dichloromethane

[0191] AcOH=acetic acid

[0192] TFA=trifluoroacetic acid

[0193] i-Pr₂NEt=diisopropylethylamine

[0194] DMAP=4-dimethylaminopyridine

[0195] NMM=N-methyl morpholine

[0196] NaHCO₃=sodium bicarbonate

[0197] NaBH(OAc)₃=sodium triacetoxyborohydride

[0198] Pd/C=palladium on carbon

[0199] EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or EDAC=3-ethyl-3

[0200] ′-(dimethylamino)propyl- carbodiimide hydrochloride (or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)

[0201] HOBT or HOBT.H₂O=1-hydroxybenzotriazole hydrate

[0202] HOAT=1-Hydroxy-7-azabenzotriazole

[0203] Pd(OAc)₂=Palladium acetate

[0204] CBZ-Cl=benzyl chloroformate

[0205] SAX=Strong Anion Exchanger

[0206] SCX=Strong Cation Exchanger

[0207] PVP=polyvinylpyridine

[0208] DCC=dicyclohexylcarbodiimide

[0209] DIC or DIPCDI=diisopropylcarbodiimide

[0210] DMA=dimethyl acetamide

[0211] DIAD=diisopropyl azodicarboxylate

[0212] DIEA=diisopropylethylamine

[0213] DIPEA=diisopropylethylamine

[0214] DPPF=l,1′-bis(diphenylphosphino)ferrocene

[0215] TEA=triethylamine

[0216] TBS=t-butyldimethylsilyl

[0217] Tf=trifluoromethanesulfonyl

[0218] L=liter

[0219] mL=milliliter

[0220] μL=microliter

[0221] g=gram(s)

[0222] h=hour(s)

[0223] mg=milligram(s)

[0224] meq=milliequivalent

[0225] min=minute(s)

[0226] rt or RT=room temperature

[0227] conc.=concentrated

[0228] sat or sat'd=saturated

[0229] TLC=thin layer chromatography

[0230] HPLC=high performance liquid chromatography

[0231] RP HPLC=reverse phase HPLC

[0232] LC/MS=high performance liquid chromatography/mass spectrometry

[0233] MS or Mass Spec=mass spectrometry

[0234] MW=molecular weight

[0235] mp =melting point

Example 12-Amino-N-{2-[2-(3-methoxy-4-oxazol-5-yl-phenylamino)-oxazol-5-yl]-benzyl}-N-methyl-acetamide

[0236]

[0237] Part A. (2-Bromo-benzyl)-methyl-amine

[0238] A solution of 2-bromobenzylbromide (9 g, 36.1 mmol) in MeOH (60ml) was added dropwise over 30 min. to a solution of methylamine in MeOH(200 mL of a 2.0 M solution, 0.4 mol). The resulting solution wasstirred at rt for 2 h and concentrated. The residue obtained wasdissolved in DCM (100 mL) and successively washed with saturated aqueoussodium carbonate, dried over sodium sulphate, and concentrated. Theresulting oil was distilled to afford the title compound (7 g, 95%) as acolorless oil (b.p. 110° C. at 0.1 mm Hg, LC/MS retention time=1.22min.; M⁺=201.92, Column: Phenominex 4.6 mm×50 mm. Solvent A=10% MeOH,90% H₂O, 10 mM NH4Ac; Solvent B=90% MeOH, 10% H₂O, 10 nM NH4Ac, Flowrate: 4 mL/min, Gradient: 0%B-100%B 4 min.).

[0239] Part B. {[(2-Bromo-benzyl)-methyl-carbamoyl]-methyl }-carbamicacid tert-butyl ester

[0240] To a solution of compound 1A (1.0 g, 5 mmol) in 50 mL of DCM wasadded N-Boc-glycine (950 mg, 5.4 mmol), followed by1-hydroxy-7-azabenzotriazole (800 mg, 5.84 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.41 g,7.38 mmol). The reaction mixture was stirred at rt for 4 hours andconcentrated under reduced pressure. The resulting oil was dissolved inEtOAc and washed successively with saturated sodium bicarbonate,1N-hydrochloric acid, dried over sodium sulfate and concentrated underreduced pressure to give the title compound (1.8 g, 99%) as a colorlessoil, which was used for the subsequent step without furtherpurification.

[0241] Part C. ({[2-(1-Ethoxy-vinyl)-benzyl]-methyl-carbamoyl}-methyl)-carbamic acid tert-butyl ester

[0242] To a solution of compound 1B (1.0 g, 2.79 mmol) in 50 mL ofdioxane was added tributyl(1-ethoxyvinyl)tin (0.976 mL, 2.70 mmol) anddichlorobis(triphenyl-phosphine)palladium(II) (0.160 g, 0.16 mmol). Thereaction mixture was equipped with a reflux condenser and heated at 100°C. for 18 hours. More dichlorobis-(triphenylphosphine)palladium(II)(0.100 g, 0.10 mmol) was added and the mixture was heated at 100° C. foranother 2 h. The mixture was cooled to rt, concentrated under reducedpressure and the residue obtained was taken up in EtOAc. A solution ofsaturated potassium fluoride was added, and the resulting mixture wasfiltered over a thin pad of Celite® into a separating funnel. Thefiltrate was washed successively with saturated potassium fluoride andwater, then dried over sodium sulfate, and concentrated under reducedpressure. The resulting oil was purified by silica gel columnchromatography to yield the title compound as an oil (0.820 g, 84%)(LC/MS retention time=3.61 min.; M⁺=349, Column: Phenominex 4.6 mm×50mm, Solvent A=10% MeOH, 90% H₂O, 10 mM NH4Ac; Solvent B=90% MeOH, 10%H₂O , 10 nM NH4Ac, Flow rate: 4 mL/min, Gradient: 0%B-100%B 4 min.).

[0243] Part D.({[2-(2-Azido-acetyl)-benzyl]-methyl-carbamoyl}-methyl)-carbamic acidtert-butyl ester

[0244] To a solution of compound 1C (3.6 g, 10.3 mmol) in THF (30 mL)and water (5 mL) was added N-bromosuccinimide (2.0 g, 11.23 mmol) andthe contents stirred at rt for 10 min. The solution was concentratedunder reduced pressure and partitioned between DCM and water. The DCMlayer was dried over sodium sulfate, concentrated under reduced pressureto yield({[2-(2-Bromo-acetyl)-benzyl]-methyl-carbamoyl}-methyl)-carbamic acidtert-butyl ester, which was then dissolved in a mixture of acetone (20mL) and water (5 mL). Sodium azide (0.737 g, 11.16 mmol) was added andthe reaction mixture stirred at 50° C. for 10 min., concentrated underreduced pressure, and partitioned between DCM and water. The DCM layerwas dried over sodium sulfate and concentrated under reduced pressure.The resulting oil was purified by silica gel column chromatography toyield the title compound as a yellow oil (2.56 g, 68%) (LC/MS retentiontime=2.90 min.; M⁺═363, Column: Phenominex 4.6 mm×50 mm, Solvent A=10%MeOH, 90% H₂O, 10 mM NH4Ac; Solvent B=90% MeOH, 10% H₂O, 10 nM NH4Ac,Flow rate: 4 mL/min, Gradient: 0%B-100%B 4 min.).

[0245] Part E. 4-Nitro-2-methoxy-((α,(αbisacetoxy)toluene

[0246] To a 5 L three-necked round bottom flask equipped with amechanical stirrer was added 4-nitro-2-methoxytoluene (150.0 g, 0.8973mol), HOAc (900 mL) and Ac₂O (900 mL). The mixture was stirred andcooled to 8° C. with an acetone/ice bath. Concentrated H₂SO₄ (136 mL)was carefully added while keeping the reaction temperature below 19° C.After cooling to 0° C., CrO₃ (252.6 g, 2.526 mol, 2.815 equiv.) wasadded portion-wise over 1 hour while maintaining the reactiontemperature between 0-10° C. After the addition, the mixture was stirredat 0° C. for 30 minutes at which time the reaction was complete. Thereaction mixture was then carefully poured into ice (1.5 kg) withstirring to give a slurry. The remaining black gummy residue was rinsedwith HOAc (3×100 mL), and the washes were added to the slurry. Afterstirring for 10 minutes, the slurry was filtered. The cake was washedwith water (3×400 mL) and suction dried for 17 hours to give compound 1E(129.0 g, 51%). ¹H NMR (CDCl₃) d 8.02 (s, 1H), 7.89 (d, J=8.4 Hz, 1H),7.77 (s, 1H), (d, 8.4 Hz, 1H), 3.98 (s; 3H), 2.16 (s, 6H).

[0247] Part F. 4-Nitro-2-methoxybenzaldehyde

[0248] To a 2 L rounded bottom flask equipped with a condenser and amechanical stirrer was placed compound 1E (250.7 g, 0.8851 mol), dioxane(300 mL) and concentrated HCl (60 mL). The reaction mixture was heatedto reflux and stirred under N₂ for 20 hours. Water (250 mL) was addeddropwise while maintaining the reaction mixture at reflux. After coolingto 0° C. with an ice/water bath, the resulting slurry was stirred for 30minutes and then filtered. The cake was washed with water (4×200 mL) andsuction dried for 17 hours to give compound 1F (146.3 g, 91%) as ayellow solid. ¹H NMR (CDCl₃) d 10.54 (s, 1H), 8.00 (d, J=8.3 Hz, 1H),7.91 (s, 1H), 7.89 (d, J=8.3 Hz, 1H), 4.08 (s, 3H).

[0249] Part G. 5-(4-Nitro-2-methoxyphenyl)oxazole

[0250] To a 5 L three-necked round bottom flask equipped with acondenser and a mechanical stirrer was placed compound 1F (146.3 g,0.8076 mol), tosylmethyl isocyanide (157.7 g, 0.8077 mol), K₂CO₃ (116.6g, 0.8075 mol) and MeOH (2.5 L). The mixture was heated to reflux underN₂ and stirred for 3 hours. Water (1.25 L) was added drop-wise whilemaintaining the pot temperature between 59-69° C. The resulting slurrywas cooled to rt, and then to 5° C. with an ice-water bath. Afterstirring for 30 minutes at 5° C, the slurry was filtered. The resultingcake was washed with water (3×400 mL) and dried in a vacuum oven at 45°C. for 20 hours to compound 1G (148.5 g, 84%) as a yellow-reddish solid.¹H NMR (CDCl₃) d 8.02 (s, 1H), 7.97 (d, J=2 Hz, 1H), 7.95 (d, J=2 Hz,1H), 7.86 (s, 1H), 7.78 (s, 1H), 4.11 (s, 3H).

[0251] Part H. 5-(4-Amino-2-methoxyphenyl)oxazole

[0252] In a 2 L hydrogenation flask was placed compound 1G (130.0 g,0.6131 mol), Pd/C (10 %, 26.2 g) and absolute EtOH (1280 mL). Themixture was hydrogenated at 35-45 psi H₂ until the reaction wascomplete. The mixture was filtered over a pad of celite (20 g) and thecake was washed with EtOH (3×100 mL). The filtrate was concentrated to avolume of 350 mL. Heptane (500 mL) was added to the resulting slurry.After stirring for 2 hours at rt, the slurry was filtered. The cake waswashed with heptane (3×100 mL) and air-dried to give 1H (80.0 g). Asecond portion of product (30.2 g) was recovered from the mother liquoraffording a total yield of 95%. ¹H NMR (CDCl₃) d 7.88 (s, 1H), 7.60 (d,J=8.4 Hz, 1H), 7.41 (s, 1H), 6.41 (dd, J=8.4, 2.1 Hz, 1H), 3.34 (d,J=2.1 Hz, 1H), 3.98 (bs, 2H), 3.94 (s, 3H).

[0253] Part I. 5-(4-Isothiocyanato-2-methoxy-phenyl)-oxazole

[0254] To a solution of 5-(4-Amino-2-methoxyphenyl)oxazole 1H (200 mg,1.05 mmol) in DCM (2 mL) was added thiocarbonyldiimizaole (224 mg, 1.26mmol) and the mixture was stirred at rt for 3 h. The mixture wasconcentrated under reduced pressure, and the residue was dissolved inMeOH (9 mL) and aliquots of 3 mL were filtered through an SCX cartridge(CUBX1HL, 500 mg cartridge, United Chemical Technologies, Bristol Pa.,USA). The filtrate was concentrated under reduced pressure to afford 440mg of the title compound which was used for the subsequent step withoutfurther purification.

[0255] Part J. Example 1

[0256] To a solution of compound 1D (0.180 g, 0.50 mmol) in 2 mL ofdioxane was added compound 1I (220 mg of crude mixture, 1 mmol) followedby triphenylphosphine (0.140 g, 0.53 mmol). The reaction mixture wasplaced in an oil bath preheated to 80° C. and stirred for 2 hour, thencooled to rt and the solvent was evaporated. The residue was treated for1 h at rt with a 1:1 mixture of TFA and DCM, and the mixture wasconcentrated under reduced pressure. The residue was dissolved in MeOH(2 mL), loaded onto an SCX cartridge (CUBX1HL, 500 mg cartridge, UnitedChemical Technologies, Bristol Pa., USA) which was washed with MeOH (3mL). The title compound was eluted from the cartridge with a 2.0 Msolution of ammonia in MeOH (3mL) and purified by preparative reversephase HPLC to yield 0.070 g of an orange oil. (LC/MS retention time=2.93min.; MH⁺=435, Column: Phenominex 4.6 mm×50 mm, Solvent A=10% MeOH, 90%H₂O, 10 mM NH4Ac; Solvent B=90% MeOH, 10% H₂O, 10 mM NH4Ac, Flow rate: 4mL/min, Gradient: 0%B-100%B 4 min.).

EXAMPLES 2-29

[0257]

[0258] Compounds having the above formula, wherein the group R has thevalues listed in Table 1, were prepared following the procedure setforth above for Example 1, using appropriately-substituted aryl orheteroaryl amine in place of 5-(4-Amino-2-methoxyphenyl)oxazole 1H.TABLE 1 HPLC time HPLC Ex. R (min) Method MH⁺ 2

2.57 c 387.3 3

3.11 c 429.3 4

3.17 c 443.32 5

2.61 c 404.29 6

3.26 b 443.23 7

3.02 b 438.15 8

2.68 b 405.21 9

2.44 b 405.21 10

2.75 b 420.21 11

2.67 b 404.21 12

3.02 b 387.21 13

2.7 b 408.18 14

1.93 b 377.16 15

2.08 b 403.22 16

2.92 b 444.19 17

3.21 a 453.81 18

3.11 a 431.98 19

2.86 a 433.95 20

3.12 a 418 21

3.12 a 418 22

2.65 a 403.02 23

2.88 a 417.03 24

2.79 a 415.01 25

2.68 b 421.23 26

2.99 b 495.18 27

2.05 b 377.2 28

3.12 b 471.2 29

1.87 b 393.17

EXAMPLES 30-48

[0259] Compounds having the formulae set forth in Table 2, were preparedfollowing the same or similar procedures to those set forth above forExamples 1-29, and/or in the general schemes previously set forthherein. In the compounds shown in Table 2, the terminal nitrogen atom onthe right-hand side is intended to designate NH₂ and the centralnitrogen atom NH. These compounds are useful in the inventive methods ofinhibiting Factor VIIa. TABLE 2 Ex. Structure 30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

We claim:
 1. A method of treating a Factor VIIa-associated condition ina mammal comprising administering to the mammal in need of treatmentthereof an effective amount of at least one compound having the formula(I),

or a pharmaceutically-acceptable salt, hydrate or prodrug thereof,wherein: A is a five or six-membered saturated or unsaturatedcarbocyclic, heterocyclic or heteroaryl ring, said ring A beingoptionally substituted with up to three groups selected from R₂₇; B isselected from one of

D is phenyl, cycloalkyl, or a five to six-membered heteroaryl orheterocyclo, provided, however, that when A is a heterocyclo orheteroaryl and a is 1, then D is phenyl or cycloalkyl; R₁ is hydrogen,C₁₋₄alkyl, or C₁₋₄alkyl substituted with one to two R₂₁; R₂ and R₃ areattached to any available carbon atom of ring B and ring D,respectively, and at each occurrence are independently selected fromhalogen, cyano, NO₂, C₁₋₆alkyl, substituted C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, haloalkyl, haloalkoxy, —OR₁₅, —C(═O)R₁₅, —OC(═O)R₁₅,—CO₂R₁₅, —OCO₂R₁₅, —C(═O)NR₁₅R₁₆, —OC(═O)NR₁₅R₁₆, —NR₁₅R₁₆,—NR₁₆C(═O)R₁₅, —NR_(16a)C(═O)NR₁₅R₁₆, —NR₁₆CO₂R₁₅, —SR₁₅, —S(O)R₁₅,—SO₂R₁₅, —SO₂NR₁₅R₁₆, —SO₃R₁₅, —NR₁₆SO₂R₁₅, and —NR_(16a)SO₂NR₁₅R₆; R₄and R₅ are independently selected from hydrogen, halogen, hydroxy,cyano, C₁₋₃alkoxy, —OCF₃, CF₃, amino, C₁₋₆alkylamino, C₁₋₄alkyl, andC₁₋₄alkyl substituted with one to two R₂₂, or alternatively, R₄ and R₅taken together may form a 3-8 membered cycloalkyl or heterocyclic spiroring, said ring being optionally substituted with up to three R₂₈; R₆ isselected from hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with one totwo R₂₃; R₇ and R₈ are independently selected from hydrogen, halogen,hydroxy, cyano, C₁₋₃alkoxy, —OCF₃, CF₃, amino, C₁₋₆alkylamino,C₁₋₄alkyl, and C₁₋₄alkyl substituted with one to two R₂₄; oralternatively, R₇ and R₈ taken together may form a 3-8 memberedcycloalkyl or heterocyclic spiro ring, said ring being optionallysubstituted with up to three R₂₉; or alternatively, one or both of R₇and R₈ may be taken together with one or both of R₉ and R₁₀ to form aheterocyclic or heteroaryl ring, said ring in turn being optionallysubstituted with up to three R₃₀; R₉ and R₁₀ are independently selectedfrom hydrogen, C₁₋₄alkyl, and C₁₋₄alkyl substituted with one to two R₂₅;or alternatively, R₉ and R₁₀ taken together may form a 3-8 memberedheterocyclic ring or a five to six membered heteroaryl ring, said ringbeing optionally substituted with up to three R₃₀; or alternatively, oneor both of R₉ and R₁₀ may be taken together with one or both of R₇ andR₈ to form a heterocyclic or heteroaryl ring optionally substituted withup to three R₃₀; R₁₁ at each occurrence is independently selected fromhalogen, cyano, NO₂, C₁₋₆alkyl, substituted C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, haloalkyl, haloalkoxy, —OR₁₃, —C(═O)R₁₃, —OC(═O)R₁₃,—CO₂R₁₃, —OCO₂R₁₃ , —C(═O)NR₁₃R₁₄, —OC(═O)NR₁₃R₁₄, —NR₁₃R₁₄,—NR₁₄C(═O)R_(13a), —NR₁₄CO₂R₁₃, —SR₁₃, —S(O)R₁₃, —SO₂R₁₃,—SO₂NR₁₃R₁₄,—SO₃R₁₃, —NR₁₄SO₂R₁₃, and —NR_(14a)SO₂NR₁₃R₁₄ or alternatively, two R₁₁groups may be taken together to form a fused benzo, heteroaryl, orheterocyclic ring, wherein said ring in turn is optionally substitutedwith up to one A group and/or one to two R₃₁; provided, however, thatR₁₁ is not alkyl substituted with —NR_(18a)C(═O)NR₁₇R₁₈; R₁₃, R₁₄, andR_(14a) at each occurrence independently of each other are selected fromhydrogen, C₁₋₆alkyl, substituted C₁₋₆alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl,C₃₋₁₀cycloalkyl(C₀₋₄alkyl), aryl(C₀₋₄alkyl), heterocyclo(C₀₋₄alkyl), andheteroaryl(C₀₋₄alkyl), wherein each of said cycloalkyl, aryl,heterocyclo, and heteroaryl groups are optionally substituted with up totwo substituents independently selected from R₃₂; provided, however,that when R₁₃ is attached to a sulfonyl group as in SO₂R₁₃, S(═O)R₁₃,and SO₃R₁₃, then R₁₃ is not hydrogen; or alternatively, R₁₃ and R₁₄ canbe taken together with the nitrogen atom to which they are attached toform a heterocyclo or heteroaryl, said ring being in turn optionallysubstituted with up to three groups selected from R₃₂; R_(13a) isselected from hydrogen, C₁₋₆alkyl, substituted C1-6alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, C₃₋₁₀cycloalkyl(C₀₋₄alkyl), aryl(C₀₋₄alkyl),heterocyclo(C₁₋₄alkyl), and heteroaryl(C₁₋₄alkyl), wherein each of saidcycloalkyl, aryl, heterocyclo, and heteroaryl groups are optionallysubstituted with up to two substituents independently selected from R₃₂;R₁₅ at each occurrence independently of each other R₁₅ is selected fromhydrogen, C₁₋₆alkyl, substituted C₁₋₆alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl,C₃₋₁₀cycloalkyl(C₀₋₄alkyl), aryl(C₀₋₄alkyl), heterocyclo(C₀₋₄alkyl), andheteroaryl(C₀₋₄alkyl), wherein each of said cycloalkyl, aryl,heterocyclo, and heteroaryl groups are optionally substituted with up totwo substituents independently selected from R₃₃; provided, however,that when R₁₅ is attached to a sulfonyl group as in SO₂R₁₅, S(═O)R₁₅,and SO₃R₁₅, then R₁₅ is not hydrogen; and R₁₆ and R_(16a) at eachoccurrence independently of each other R₁₆ and R_(16a) are selected fromhydrogen, C₁₋₆alkyl, substituted C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,—OR₁₉, —C(═O)R₁₉, —CO₂R₁₉, —SO₂R₁₉, C₃₋₁₀cycloalkyl(C₀₋₄alkyl),aryl(C₀₋₄alkyl), heterocyclo(C₀₋₄alkyl), and heteroaryl(C₀₋₄alkyl),wherein R₁₉ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, aryl, heterocyclo, orheteroaryl, and each of said R₁₉, cycloalkyl, aryl, heterocyclo, andheteroaryl groups are in turn optionally substituted with up to twosubstituents independently selected from R₃₄; alternatively, R₁₅ and R₁₆can be taken together with the nitrogen atom to which they are attachedto form a heterocyclo or heteroaryl, said ring being in turn optionallysubstituted with up to three groups selected from R₃₄; R₁₇ and R₁₈ areindependently selected from hydrogen, alkyl, substituted alkyl, cyano,hydroxy, alkoxy, cycloalkyl, heterocyclo, aryl and heteroaryl, or takentogether may form a heteroaryl or heterocyclo ring; R_(17a) is hydrogen,alkyl, or substituted alkyl; R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, and R₂₆ areindependently selected from halogen, cyano, hydroxy, C₁₋₃alkoxy, OCF₃,CF₃, amino, and C₁₋₆alkylamino; R₂₇, R₂₈, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, andR₃₄ are at each occurrence independently selected from C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, oxo (═O), halo(C₀₋₄alkyl), NO₂(C₀₋₄alkyl),hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl), cyano(C₀₋₄alkyl),amino(C₀₋₄alkyl), C₁₋₄alkoxy(C₀₋₄alkyl), —C₁₋₆alkylamino(C₀₋₄alkyl),C₁₋₄alkylthio(C₀₋₄alkyl), carbamyl(C₀₋₄alkyl),—C(═O)C₁₋₄alkyl,—CO₂C₁₋₄alkyl, —S(O)(C₁₋₄alkyl), —SO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄alkyl), —SO₃H, —SO₃(C₁₋₄alkyl), —NHCO(C₁₋₆alkyl), and—C(═O)NH(C₁₋₄alkyl), provided, however, that when R₂₆, R₂₇, R₃₀, R₃₁,R₃₂, R₃₃, and R₃₄ are substituents attached to an aryl or heteroarylring, said groups are not selected from oxo (═O); provided further, thatwhen R₂₆, R₂₇, R₃₀, R₃₁, R₃₂, R₃₃, and R₃₄ are hydroxy and attached toan aryl or heteroaryl ring, the ring may undergo tautomerization to anoxo species, or exist as an equilibrium mixture of both tautomers; a is0 or 1; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; p is 0, 1 or 2; and q is0, 1, 2, 3 or
 4. 2. The method according to claim 1, comprisingadministering to the mammal a compound having the formula (Ib),

or a pharmaceutically-acceptable salt, hydrate or prodrug thereof,wherein: B is

R₂ and R₃ are attached to any available carbon atom of ring B and ringD, respectively, and at each occurrence are independently selected fromhalogen, cyano, C₁₋₄ alkyl, hydroxy(C₁₋₄alkyl), CF₃(C₀₋₄alkyl),OCF₃(C₀₋₄alkyl), cyano(C₁₋₄alkyl), amino(C₀₋₄alkyl),C₁₋₄alkoxy(C₀₋₄alkyl), C₁₋₆alkylamino(C₀₋₄alkyl), andC₁₋₄alkylthio(C₀₋₄alkyl); R₄ and R₅ are independently selected fromhydrogen and C₁₋₄alkyl; R₆ is selected from C₁₋₄alkyl; R₉ and R₁₀ , areindependently selected from hydrogen, C₁₋₄alkyl, and C₁₋₄alkylsubstituted with one to two R₂₅; or alternatively, R₉ and R₁₀ takentogether may form a 3-8 membered heterocyclic ring or a five to sixmembered heteroaryl ring, said ring being optionally substituted with upto three R₃₀; R₁₁ at each occurrence is independently selected fromhalogen, cyano, C₁₋₄alkyl, hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl),OCF₃(C₀₋₄alkyl), cyano(C₁₋₄ alkyl), amino(C₀₋₄alkyl),C₁₋₄alkoxy(C₀₋₄alkyl), C₁₋₆alkylamino(C₀₋₄alkyl), and C₁₋₄alkylthio(C₀₋₄alkyl), or two R₁₁ groups may be taken together to form afused benzo, heteroaryl, or heterocyclic ring, wherein said ring in turnis optionally substituted with a group A or one to two of C₁₋₄alkyl,oxo(═O), halogen, cyano, trifluoromethyl, or trifluoromethoxy; R₃₀ ateach occurrence is independently selected from C₁₋₄alkyl, oxo (═O),halo(C₀₋₄alkyl), hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl),cyano(C₀₋₄alkyl), amino(C₀₋₄alkyl), C₁₋₄alkoxy(C₀₋₄alkyl),C₁₋₆alkylamino(C₀₋₄alkyl), C₁₋₄alkylthio(C₀₋₄alkyl), —C(═O)C₁₋₄alkyl,and —CO₂C₁₋₄ alkyl; m is 0 or 1;and q is 0, 1, or
 2. 3. The methodaccording to claim 1, comprising administering to the mammal a compoundof formula (I), or a pharmaceutically-acceptable salt, hydrate orprodrug thereof, wherein: A is selected from phenyl, oxazolyl,thiazolyl, isothiazolyl, imidazolyl, furyl, thienyl, thiadiazolyl,oxadiazolyl, tetrazolyl, triazolyl, diazolyl, pyrrolyl, and pyrazolyl,said ring A being optionally substituted with up to two groups selectedfrom halogen, C₁₋₄alkyl, haloalkyl, haloalkoxy, OH, C₁₋₄alkoxy,C₁₋₄alkylcarbonyl, CN, NH₂, NH(C₁₋₄alkyl), and N(alkyl)₂; and a is
 1. 4.The method according to claim 1, comprising administering to the mammala compound of formula (I), or a pharmaceutically-acceptable salt,hydrate or prodrug thereof, wherein: B is


5. The method according to claim 4, comprising administering to themammal a compound of formula (I), or a pharmaceutically-acceptable salt,hydrate or prodrug thereof, wherein m is
 0. 6. The method according toclaim 1, comprising administering to the mammal a compound of formula(I), or a pharmaceutically-acceptable salt, hydrate or prodrug thereof,in which R₃ is selected from C₁₋₄alkyl and halogen, or n is
 0. 7. Themethod according to claim 1, comprising administering to the mammal acompound of formula (I), or a pharmaceutically-acceptable salt, hydrateor prodrug thereof, in which D is selected from phenyl, pyridyl, phenyl,pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, and pyrrolyl. 8.The method according to claim 1, comprising administering to the mammala compound of formula (I), or a pharmaceutically-acceptable salt,hydrate or prodrug thereof, in which R₄ and R₅ are hydrogen orC₁₋₄alkyl.
 9. The method according to claim 1, comprising administeringto the mammal a compound of formula (I), or apharmaceutically-acceptable salt, hydrate or prodrug thereof, in whichR₆ is C₁₋₄alkyl.
 10. The method according to claim 1, comprisingadministering to the mammal a compound of formula (I), or apharmaceutically-acceptable salt, hydrate or prodrug thereof, in whichR₇ and R₈ are hydrogen or C₁₋₄alkyl.
 11. The method according to claim1, comprising administering to the mammal a compound of formula (I), ora pharmaceutically-acceptable salt, hydrate or prodrug thereof, in whichR₉ and R₁₀ are hydrogen or C₁₋₄alkyl.
 12. A method of treating a FactorVIIa-associated condition in a mammal comprising administering to themammal in need of treatment thereof an effective amount of a compoundhaving the formula (Ia),

or a pharmaceutically-acceptable salt, hydrate, or prodrug thereof, inwhich: A is selected from phenyl, oxazolyl, thiazolyl, isothiazolyl,imidazolyl, furyl, thienyl, thiadiazolyl, oxadiazolyl, tetrazolyl,triazolyl, diazolyl, pyrrolyl, and pyrazolyl, said ring A beingoptionally substituted with up to two groups selected from halogen, NO₂,C₁₋₄alkyl, haloalkyl, haloalkoxy, OH, C₁₋₄alkoxy, C₁₋₄alkylcarbonyl, CN,NH₂, NH(C₁₋₄alkyl), and N(alkyl)₂; D is phenyl, or when A is phenyl, Dis selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl,thiophenyl, and pyrrolyl; R_(2a) is selected from hydrogen, halogen,C₁₋₄alkyl, hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl),cyano(C₀₋₄alkyl), amino(C₀₋₄alkyl), C₁₋₃alkoxy(C₀₋₄alkyl), andC₁₋₆alkylamino(C₀₋₄alkyl); R₃ is selected from hydrogen, halogen,C₁₋₄alkyl, hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl),cyano(C₀₋₄alkyl), amino(C₀₋₄alkyl), C₁₋₃alkoxy(C₀₋₄alkyl), andC₁₋₆alkylamino(C₀₋₄alkyl); R₁₁ is selected from hydrogen, halogen,C₁₋₄alkyl, hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl),cyano(C₀₋₄alkyl), amino(C₀₋₄alkyl), C₁₋₃alkoxy(C₀₋₄alkyl), andC₁₋₆alkylamino(C₀₋₄alkyl), or two R₁₁ groups may be taken together toform a fused benzo, heteroaryl, or heterocyclic ring, wherein said ringin turn is optionally substituted with up to one A group and/or one totwo R₃₁; R₆ is C₁₋₄alkyl; R₉ and R₁₀ are independently selected fromhydrogen and C₁₋₄alkyl; R₃₁ is selected from hydrogen, halogen,C₁₋₄alkyl, hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl),cyano(C₀₋₄alkyl), and C₁₋₄alkoxy(C₀₋₄alkyl); a is 0 or 1; n is 0, 1, 2,3, or 4; p is 0, 1 or 2; and q is 0, 1 , or
 2. 13. The method of claim12, comprising administering to the mammal a compound of formula (Ia),wherein: A is oxazolyl; D is phenyl; R_(2a) is hydrogen, halogen, orC₁₋₄alkyl; R₃ is hydrogen, halogen, or C₁₋₄alkyl; and p is
 1. 14. Themethod of claim 13, comprising administering to the mammal a compound offormula (Ia), wherein: R₆ is methyl; and R₉ and R₁₀ are hydrogen. 15.The method of claim 1 in which the Factor VIIa associated disorder isselected from myocardial infarction, unstable angina, thromboembolicstroke, venous thrombosis, pulmonary embolism, peripheral occlusivearterial disease, atherosclerotic vascular disease, atherscleroticplaque rupture, and/or thromboembolic consequences of surgery,interventional cardiology, or immobility.
 16. The method of claim 1comprising administering to the mammal (a) at least one compound havingthe formula (I) according to claim 1, or a salt, hydrate or prodrugthereof; and (b) at least one additional therapeutic agent selected fromone or more of an immunosuppressant, an anti-thrombotic agent, ananti-viral agent, an anti-inflammatory agent, an anti-fungal agent, anantibiotic, an anti-vascular hyperproliferation compound, and a serineprotease inhibitor.
 17. The method of claim 13 in which the Factor VIIaassociated disorder is selected from myocardial infarction, unstableangina, thromboembolic stroke, venous thrombosis, pulmonary embolism,peripheral occlusive arterial disease, atherosclerotic vascular disease,athersclerotic plaque rupture, and/or the thromboembolic consequences ofsurgery, interventional cardiology, or immobility.
 18. A compound havingthe formula (II),

or a pharmaceutically-acceptable salt, hydrate, or prodrug thereof,wherein A is selected from phenyl, oxazolyl, thiazolyl, isothiazolyl,imidazolyl, furyl, thienyl, thiadiazolyl, oxadiazolyl, tetrazolyl,triazolyl, diazolyl, pyrrolyl, and pyrazolyl, said ring A beingoptionally substituted with up to two groups selected from halogen, NO₂,C₁₋₄alkyl, haloalkyl, haloalkoxy, OH, C₁₋₄alkoxy, C₁₋₄alkylcarbonyl, CN,NH₂, NH(C₁₋₄alkyl), and N(alkyl)₂; R₃ is selected from hydrogen,halogen, C₁₋₄alkyl, hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl),cyano(C₀₋₄alkyl), amino(C₀₋₄alkyl), C₁₋₃alkoxy(C₀₋₄alkyl), andC₁₋₆alkylamino(C₀₋₄alkyl); R₁₁ is selected from hydrogen, halogen,C₁₋₄alkyl, hydroxy(C₀₋₄alkyl), CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl),cyano(C₀₋₄alkyl), amino(C₀₋₄alkyl), C₁₋₃alkoxy(C₀₋₄alkyl), andC₁₋₆alkylamino(C₀₋₄alkyl), or two R₁₁ groups may be taken together, orone of R₁₁ may be taken together with R_(11a) to form a fused benzo,heteroaryl, or heterocyclic ring, wherein said ring in turn isoptionally substituted with a group A or one to two of C₁₋₄alkyl,oxo(═O), halogen, cyano, trifluoromethyl, or trifluoromethoxy; R_(11a)is selected from hydrogen, halogen, C₁₋₄alkyl, hydroxy(C₀₋₄alkyl),CF₃(C₀₋₄alkyl), OCF₃(C₀₋₄alkyl), cyano(C₀₋₄alkyl), andC₁₋₄alkoxy(C₀₋₄alkyl), or R_(11a) may be taken together with R₁₁ to forma fused benzo, heteroaryl, or heterocyclic ring, wherein said ring inturn is optionally substituted with a group A or one to two ofC₁₋₄alkyl, oxo(═O), halogen, cyano, trifluoromethyl, ortrifluoromethoxy; a is 0 or 1; and n is 0, 1, 2, 3, or 4; and saidcompound of formula (II) is effective in inhibiting Factor VIIa in amammal with an IC₅₀ of less than 1 μM.
 19. A compound according to claim18, having the formula,

or a pharmaceutically-acceptable salt, hydrate, or prodrug thereof,wherein said compound is effective in inhibiting Factor VIIa in a mammalwith an IC₅₀ of less than 500 nM.